Lysine Acetylation and the Regulation of Vasopressin/Aquaporin System in the Principal Cell

摘要 精氨酸加压素(AVP)和水通道的调节失调，称为水通道蛋白(AQPs)，可导致多种 临床上严重的水电解质问题，从严重脱水到低钠血症。这个 AVP在肾脏的作用主要是通过AVP受体2(AVPR2)在肾脏主体上介导的 手机。AVP敏感的水通道，AQP2和AQP3，促进水分重吸收，防止脱水。 在这样做的过程中，这些水通道起到了浓缩尿液的作用。基于令人信服的初步数据， 这项建议集中在第一个报道的AQP3的修饰，赖氨酸282乙酰化，在调节 基材渗透率。赖氨酸乙酰化对基因表达也很重要，它是通过 乙酰转移酶和脱乙酰酶(HDACs)酶。我们最近进行了一次系统的审查， 荟萃分析并确定慢性使用HDAC抑制剂，就像在癌症治疗中发生的那样，导致 显著&gt；2人类体液电解质紊乱的赔率比。因此，确定功能 肾脏中赖氨酸乙酰化的意义无论从生理学角度还是在肾脏中都是至关重要的 了解HDAC抑制对水电解质平衡的临床影响。共同努力，我们令人信服的 初步数据使我们提出了肾脏AVPR2/AQP调节的首要假设 赖氨酸乙酰化轴在调节尿液浓缩能力和液体平衡方面起着关键作用。这将会被测试 目标1：验证AQP3赖氨酸乙酰化增加底物通量的假设 在主细胞中促进尿液浓度。目的2：检验HDAC1和HDAC2的假设 调节主细胞中AVPR2/AQP轴的转录。我们将结合不偏不倚的系统生物学 从细胞到整体动物实验填补我们对注意力集中理解中的关键空白的方法 这可能会为治疗水电解质紊乱提供新的治疗途径。

SUMMARY Dysregulation of arginine vasopressin (AVP) and water channels, called aquaporins (AQPs), can lead to a variety of clinically-significant water-electrolyte problems, ranging from severe dehydration to low plasma sodium. The actions of AVP in the kidney are mediated via the AVP receptor 2 (AVPR2) predominantly on the kidney principal cell. The AVP-sensitive water channels, AQP2 and AQP3, promote water reabsorption to prevent dehydration. In doing so these water channels function to concentrate the urine. Based on our compelling preliminary data, this proposal focuses on the first reported modification of AQP3, lysine 282 acetylation, in the regulation of substrate permeability. Lysine acetylation is also important for gene expression and it is regulated via acetyltransferases and deacetylases (HDACs) enzymes. We recently performed a systemic review and metanalysis and determined that chronic HDAC inhibitor use, as occurs in the treatment of cancers, results in a significant >2 odds ratio of experiencing fluid-electrolyte disorders in humans. Thus, determining the functional significance of lysine acetylation in the kidney is critically important both from a physiological perspective and in understanding the clinical impact of HDAC inhibition on water-electrolyte balance. Together, our compelling preliminary data have led us to formulate the overarching hypothesis that regulation of the kidney AVPR2/AQP axis by lysine acetylation is critical in regulating urinary concentrating ability and fluid balance. This will be tested by the following two aims: Aim 1: To test the hypothesis that lysine acetylation of AQP3 increases substrate flux in the principal cell promoting urine concentration. Aim 2: To test the hypothesis that HDAC1 and HDAC2 regulate the transcription of the AVPR2/AQP axis in the principal cell. We will combine unbiased, system biology approaches with cell to whole animal experiments to close key gaps in our understanding of concentrating mechanisms in the kidney and may reveal new therapeutic avenues to treat fluid-electrolyte disorders.